Abstract

CD4+ T cells and B cells contribute to inflammation in the joints of rheumatoid arthritis (RA) patients, but the precise roles of these lymphocytes in disease pathogenesis are not known. A recent report by Rao et al. characterizes a newly defined subset of CD4+ T cells that are expanded in RA joints and are likely peripheral helpers of autoreactive B cells.

Synovial tissues and fluid sampled from seropositive RA patients (i.e., with anti-Ig Fc or anti–citrullinated peptide autoantibodies) and from seronegative patients were analyzed by mass cytometry, fluorescence flow cytometry, reverse transcription polymerase chain reaction, and unbiased RNA sequencing. About 25 to 30% of the CD4+ T cells from seropositive patient samples expressed high levels of programmed cell death protein-1 (PD-1), five times the number in seronegative patient samples. Unlike T follicular helper (TFH) cells, which express PD-1 and CXCR5, the expanded PD-1hi T cells were CXCR5 negative. PD-1hiCXCR5− CD4+ T cells were also detected in the blood of seropositive patients, and their numbers correlated with disease activity.

The PD-1hiCXCR5− T cells from the RA patients expressed much more IL-21 and CXCL13 than PD-1− cells, as well as many of the genes important in T-B collaboration that TFH cell express. Unlike TFH cells, PD-1hiCXCR5− T cells had high BLIMP1and low BCL6 expression and also expressed the inflammatory chemokine receptors CCR2, CX3CR1, and CCR5. Coculture experiments demonstrated that the PD-1hiCXCR5− T cells supported B cell differentiation into plasma cells and IgG secretion. Immunofluorescence studies of synovial tissues showed that many of these PD-1hiCXCR5− T cells were adjacent to B cells, inside and outside lymphoid aggregates.

The T cells in the joints RA patients described in this study, which the authors call T peripheral helper (TPH) cells, have the functional properties of TFH cells found in secondary lymphoid organs, and the migratory phenotype of effector T cells found in inflamed tissues. Thus, it appears they are highly qualified to provide T cell help for local autoantibody production in the rheumatic joint. TPH cells may be important to the development of germinal centers in tertiary lymphoid organs, a characteristic feature of the synovium in RA. The presence of TPH cells in other chronic autoimmune diseases and the role of these cells in disease pathogenesis remain to be determined.